Combining robotics with enhanced serotonin-driven cortical plasticity improves post-stroke motor recovery.

Despite recent progresses in robotic rehabilitation technologies, their efficacy for post-stroke motor recovery is still limited. Such limitations might stem from the insufficient enhancement of plasticity mechanisms, crucial for functional recovery. Here, we designed a clinically relevant strategy that combines robotic rehabilitation with chemogenetic stimulation of serotonin release to boost plasticity. These two approaches acted synergistically to enhance post-stroke motor performance. Indeed, mice treated with our combined therapy showed substantial functional gains that persisted beyond the treatment period and generalized to non-trained tasks. Motor recovery was associated with a reduction in electrophysiological and neuroanatomical markers of GABAergic neurotransmission, suggesting disinhibition in perilesional areas. To unveil the translational potentialities of our approach, we specifically targeted the serotonin 1A receptor by delivering Buspirone, a clinically approved drug, in stroke mice undergoing robotic rehabilitation. Administration of Buspirone restored motor impairments similarly to what observed with chemogenetic stimulation, showing the immediate translational potential of this combined approach to significantly improve motor recovery after stroke.

Assessment of heart rate variability changes during dipyridamole infusion and dipyridamole-induced myocardial ischemia: a time variant spectral approach.

OBJECTIVES: We sought to evaluate changes in RR interval variability during dipyridamole infusion and dipyridamole-induced myocardial ischemia. BACKGROUND: Myocardial ischemia and the autonomic nervous system can be mutually interdependent. Spectral analysis of RR interval variability is a useful tool in assessing autonomic tone. METHODS: We used a time variant autoregressive spectral estimation algorithm that could extract spectral variables even in the presence of nonstationary signals. Two groups were considered: group A (patients with ischemia, n = 15) with effort or mixed angina, angiographically assessed coronary artery disease and positive exercise and dipyridamole echocardiographic test results, and group B (control subjects, n = 10) with normal exercise and dipyridamole echocardiographic test results. We investigated the following variables: RR interval mean and variance, low frequency (LF) and high frequency (HF) power in normalized units, LF ratio (LF/LFbasal power), HF ratio (HF/HFbasal power) and LF/HF ratio. For each test epoch, we calculated for group A and group B the mean value +/- SE of all indexes considered. Differences due to an effect either of group (ischemic vs. control) or of time (including both drug and ischemia effects) were analyzed by using analysis of variance for repeated measurements. RESULTS: Dipyridamole injection was characterized by a reduction of all spectral components in negative test. The LF ratio was the only variable able to discriminate patients with ischemia from control subjects (p < 0.05), whereas a time effect was evident for both mean RR interval and high frequency power in normalized units (p < 0.05). The LF ratio decreased in group B from 1 +/- 0.00 (basal) to 0.31 +/- 0.22 (peak), and increased in group A from 1 +/- 0.00 to 15.41 +/- 6.59, respectively. Results of an unpaired t test comparing the peak values of the two groups were also statistically significant (p < 0.01). CONCLUSIONS: Our data show that time variant analysis of heart rate variability evidences an increase in the low frequency ratio that allows differentiation of positive from negative test results, suggesting that the electrocardiogram may contain ischemia information unrelated to ST-T variations, even if their enhancement requires a more complex data processing procedure.

Existence of anticorrelations for local field potentials recorded from mice reared in standard condition and environmental enrichment.

In the present paper, we analyze local field potentials (LFPs) recorded from the secondary motor cortex (M2) and primary visual cortex (V1) of freely moving mice reared in environmental enrichment (EE) and standard condition (SC). We focus on the scaling properties of the signals by using an integrated approach combining three different techniques: the Higuchi method, detrended fluctuation analysis, and power spectrum. Each technique provides direct or indirect estimations of the Hurst exponent H and this prevents spurious identification of scaling properties in time-series analysis. It is well known that the power spectrum of an LFP signal scales as 1/f(ß) with ß>0. Our results indicate the existence of a particular power spectrum scaling law 1/f(ß) with ß<0 for low frequencies (f<4 Hz) for both SC and EE rearing conditions. This type of scaling behavior is associated to the presence of anticorrelation in the corresponding LFP signals. Moreover, since EE is an experimental protocol based on the enhancement of sensorimotor stimulation, we study the possible effects of EE on the scaling properties of secondary motor cortex (M2) and primary visual cortex (V1). Notably, the difference between Hurst's exponents in EE and SC for individual cortical regions (M2) and (V1) is not statistically significant. On the other hand, using the detrended cross-correlation coefficient, we find that EE significantly reduces the functional coupling between secondary motor cortex (M2) and visual cortex (V1).

Co-receptor usage of HIV-1 primary isolates, viral burden, and CCR5 genotype in mother-to-child HIV-1 transmission.

OBJECTIVE: To investigate the relationship between CC chemokine receptor 5 (CCR5) genotype, viral load and co-receptor usage of maternal HIV-1 isolates in perinatal HIV-1 transmission. PATIENTS AND METHODS: A total of 181 mothers and infants were studied at the time of delivery. Wild-type (wt) and delta32 CCR5 alleles were determined by means of polymerase chain reaction (PCR). The viral load in maternal plasma samples was determined by a quantitative reverse transcriptase-PCR assay; co-receptor usage of maternal isolates was determined by viral infection in cells stably expressing CCR5 or CXC chemokine receptor 4 (CXCR4) co-receptors. RESULTS: HIV-1 transmission rates in wt/wt and wt/delta32 mothers (14.7 versus 15.8%), and in wt/wt and wt/delta32 infants (14.6 versus 14.3%) were similar. Mothers transmitting infection to wt/delta32 infants had significantly higher HIV-1-RNA levels than those who transmitted infection to wt/wt infants (5.4 versus 4.1 log10 copies/ml, P = 0.03). In wt/wt children there was a positive relationship between transmission rate and maternal viral load over the entire range of HIV-1 values, whereas in wt/delta32 children transmission occurred only at viral loads greater than 4.0 log10 copies/ml. Logistic regression analysis confirmed that the relationship between viral load and transmission varied according to the child's CCR5 genotype (P = 0.035; adjusted for zidovudine prophylaxis and mode of delivery, P = 0.090). Moreover, the majority of wt/wt transmitting mothers had R5-type isolates, whereas none of the wt/delta32 mothers with an R5-type virus transmitted HIV-1 to their wt/delta32 infants. CONCLUSION: Taken together, these findings suggest that CCR5 delta32 heterozygosity exerts a protective effect against perinatal transmission in children exposed to a low maternal viral burden of an R5-type isolate.

Restriction of HIV type 1 infection in macrophages heterozygous for a deletion in the CC-chemokine receptor 5 gene.

Homozygosity for a 32-base pair deletion (delta32) within the CC-chemokine receptor 5 (CCR5) gene confers resistance to infection by R5-type HIV-1 isolates. To ascertain how CCR5delta32 heterozygosity influences the susceptibility of lymphocytes and macrophages to HIV-1 infection, peripheral blood lymphocytes (PBLs) and monocyte-derived macrophages (MDMs) from three HIV-1-uninfected CCR5delta32 heterozygous infants and three HIV-1-uninfected CCR5 wild-type homozygous infants were exposed to two R5-type primary isolates. HIV-1 infection was monitored by DNA-PCR and p24 antigen determination; CCR5 and CCR5delta32 transcripts were quantified by competitive reverse transcription-PCR. Wild-type homozygous MDMs and PBLs and heterozygous PBLs were infected by both viral isolates, albeit with different efficiencies, but heterozygous MDMs showed restriction to HIV-1 infection. Lower levels of CCR5 mRNA and protein expression were found in heterozygous versus wild-type homozygous MDMs and PBLs. Interestingly, wild-type homozygous MDMs showed higher levels of CCR5 mRNA expression compared with wild-type homozygous PBLs, while heterozygous MDMs had lower levels of CCR5 wild-type mRNA and a higher CCR5delta32/CCR5 mRNA ratio compared with heterozygous PBLs. These findings suggest that CCR5delta32 heterozygosity confers a different degree of protection against HIV-1 in PBLs and MDMs, depending on the ratio of wild-type and mutant CCR5 mRNA in the two cell types, and may delay virus spread in the host by preventing infection of monocytes and macrophages.

Comparing different forms of male and female aggression in wild and laboratory mice: an ethopharmacological study.

The purpose of this study was to compare the effects of 2 mg/kg fluprazine (a serotonergic psychoactive drug with antiaggressive properties) on intrasexual attack, infanticide, and predation (on an insect larva) in males and females of wild and Swiss mice. The results showed that, in both stocks of mice, fluprazine significantly inhibited intrasexual and infanticidal attack in both sexes, but predatory attack was not altered by the drug treatment. Motivational and neural substrates underlying intrasexual attack and infanticide appear, thus, to be related to each other, and similarly modulated in both males and females. Conversely, predatory attack seems to be under a different neurohumoral control. The similar regulation of proximal mechanisms of aggressive behavior observed in wild and Swiss mice suggests a common neurobiology of aggression. For this reason, the outbred laboratory Swiss mice appear to be a reliable model for studies on causal and functional mechanisms of aggression.

The inhibitory effects of fluprazine on parental aggression in female mice are dependent upon intruder sex.

Lactating resident mice respond differently to male and female intruder conspecifics, showing defensive attack towards the former and offensive attack towards the latter. The effects of fluprazine (1-5 mg/kg) on this differential response pattern have been assessed. Although fluprazine increased the latencies of attack on male intruders, a very much more potent inhibitory effect was observed on attacks directed towards female intruders. Fluprazine also modestly reduced social investigation of female intruders and increased nest-oriented behaviour irrespective of the intruder's sex. As the pattern of attack on intruders, exploration, fear responses and maintenance behaviour all remained largely intact under drug treatment, it seems unlikely that the drug's inhibitory action on attack involves fear potentiation and/or olfactory impairment. It is suggested that the greater sensitivity of offensive attack to the inhibitory actions of fluprazine may reflect the relative degree of threat to resident parental investment posed by male and female conspecific intruders.

Kinship and familiarity as factors affecting social transfer of food preferences in adult Mongolian gerbils (Meriones unguiculatus).

Experiments were carried out with Mongolian gerbils (Meriones unguiculatus) to assess whether a socially mediated acquisition of diet selection exists in this species. Results showed that a gerbil was influenced in its diet choices by information extracted during a brief period of interaction with a familiar conspecific that had recently eaten a novel food. Data revealed that the acquisition of a food preference from a conspecific depends on the existence of a social bond between the interacting gerbils. Either genetic relatedness (being brother or sister raised in different litters) or familiarity (being bred in the same litter or being member of a reproductive pair) is necessary for the transfer of information. Unfamiliar and unrelated observer gerbils did not selectively choose their demonstrator's food.

Social learning of a food preference in male and female Mongolian gerbils is facilitated by the anxiolytic, chlordiazepoxide.

Social transmission of a food preference in Mongolian gerbils (Meriones unguiculatus) depends on the presence of a social bond between the interacting animals. An "observer" gerbil can acquire a preference for a novel food item from a familiar and, or related "demonstrator" animal. However, exposure to an unfamiliar and unrelated demonstrator gerbil does not lead to acquisition of a food preference, even though the extent of social interaction and likelihood of transmission of food information is unaffected. Likewise, individual preexposure to a novel food does not affect diet preference in individual animals. Here we show that oral, nongavage, administration of the benzodiazepine anxiolytic, chlordiazcpoxide (CDP, 2.5, 5, and 10 mg/kg) has significant dose-associated differential facilitatory effects on social learning in male and female gerbils, while having no significant effects on either individual learning or total food consumption. These results suggest that the CDP mediated reduction of the anxiety associated with the interactions between unfamiliar/unrelated gerbils facilitates social learning. These findings also rise the possibility of sex differences in socially related anxiety and the effects of CDP on social learning in gerbils.

Time-variant power spectrum analysis for the detection of transient episodes in HRV signal.

A time-variant algorithm of autoregressive (AR) identification is introduced and applied to the heart rate variability (HRV) signal. The power spectrum is calculated from the AR coefficients derived from each single RR interval considered. Time-variant AR coefficients are determined through adaptive parametric identification with a forgetting factor which obtains weighed values on a running temporal window of 50 preceding measurements. Power spectrum density (PSD) is hence obtained at each cardiac cycle, making it possible to follow the dynamics of the spectral parameters on a beat-by-beat basis. These parameters are mainly the LF (low frequency) and the HF (high frequency) powers, and their ratio LF/HF. These together account for the balanced sympatho-vagal control mechanism affecting the heart rate. This method is applied to subjects suffering from transient ischemic attacks. The time variant spectral parameters suggest an early activation of LF component in the HRV power spectrum. It precedes by approximately 1.5-2 min the tachycardia and the ST displacement, generally indicative of the onset of an ischemic episode. The results suggest an arousal of sympathetic system before the acute attack.

Maternal influences on food preferences in weanling mice Mus domesticus.

This study has been designed to evaluate the role of social (maternal) influences on the development of feeding behaviour in mice. A large enclosure, allowing direct observation, was divided into three separate areas: a central area for the nest and two side feeding areas at opposite ends. In one the young could feed with their mother, in the other one the young had to feed on their own. Three different groups were studied: one had the same food in the two feeding areas: the second had a less palatable food in the mother feeding area: the third had two different kinds of food with similar palatability in the feeding areas. The development of infants' behaviour expressed as: a) order of exit from the nest; b) first direction taken on leaving the nest; c) first food consumed: d) frequency of contacts with mother or pup food was electronically recorded and analysed. The results clearly show that weanling mice strongly prefer to follow their mother at her feeding sites even when the mother's food is less palatable than their own. Furthermore infants of one group, in a following binary choice test, preferred to eat the food they experienced in the mum's feeding area instead of what they experienced in their own feeding area. The fitness of such behaviour in more natural situations is discussed.

The effect of demonstrator age and number on duration of socially-induced food preferences in house mouse (Mus domesticus).

Present research was undertaken to investigate whether the transfer of food preference from a demonstrator mouse to an observer can be influenced by their relative age. In experiment 1 an adult female mouse, the observer, was allowed to interact with a recently-fed demonstrator which was a pup of her litter or an adult female mouse. The observer was then tested to assess whether it acquired a preference for the demonstrator's diet. The results showed that a pup demonstrator's influence on an adult's food preference is shorter-lasting than an adult demonstrator's influence. Experiment 2 was aimed to investigate whether many demonstrators have an additive effect in influencing their observer's choice. The results indicated that multiple pup demonstrations do not increase longevity of food preferences induced by pup demonstrators. Moreover, the longevity of an adult observer's preference for its demonstrator's food is reduced by the exposure to multiple adult demonstrators. Results are discussed in terms of demonstrator's reliability and of social constraints that could affect social transfer of food information in the house mouse.

Hypothalamic levels of LHRF in male mice of differing social status and from individual housing.

Swiss male mice were individually-housed or maintained in groups of 8 from weaning until 80 days of age. At this time, the grouped mice were allocated to new groups of 5-6 previously unfamiliar individuals. Identified dominants were then caged with two clearly submissive males for 1 week. At this time hypothalamic samples were taken from the dominant and one subordinate and from a number of long-term individually-housed males. A radio- immunoassay for LHRF was carried out. The levels of this hypothalamic releasing factor were significantly higher in both dominant and subordinate grouped mice than in 'isolates'. Mice of differing social status showed comparable titres of this hormone. The results suggest that social conflict and/or disturbance augments this factor in mice irrespective of the social status achieved by individual animals.

Hypothalamic levels of thyrotropin-releasing hormone (TRH) in male albino mice of different social status.

Hypothalamic levels of TRH were contrasted in identified dominant and submissive (housed together for 4 days) Swiss male mice and undisturbed 'isolated' counterparts. Both dominants and submissives had significantly higher titres of this hormone than the 'isolates', suggesting that the experience of fighting relatively elevates the concentration of this factor in both winners and losers. It seems likely that titres of TRH are modified by fighting experience and these factors may alter subsequent behaviour but more investigation is needed on this topic.

Ethology and veterinary science.

After a brief introduction on the scope and methods of ethology, this review analyses the development of the concepts of normal and pathological behaviour in accordance with the ethological approach. Finally there is a discussion on the possible functions of ethology in the veterinary field.